This is a multi-site collaborative R01 application from The Research Units on Pediatric Psychopharmacology [RUPP] Autism Network (Indiana University, Seattle Children's Research Institute, UCLA, and Yale University). Autism is a major public health concern throughout the world. The cost of the disability is estimated to be more than $30 billion annually in the U.S. alone. Recent data indicate that as many as 50% of children with pervasive developmental disorders (PDDs) have moderate to severe problems of hyperactivity and impulsiveness. The impact of these symptoms may be profound and make the child less able to make use of educational and behavioral interventions. Consensus is lacking on how to treat children with PDD accompanied by hyperactivity. Compared to typically developing children with ADHD, children with PDD often show less benefit and greater side effect burden. Guanfacine is commonly used in this population, but poorly studied. Our pilot data indicate that guanfacine is a promising treatment for hyperactivity in children with PDD with a good tolerability profile. In addition, we have identified biomarkers (genetic and neurochemical) that may be associated with positive effects. For these reasons, we chose guanfacine for the proposed rigorous and possibly definitive study in this population. The study involves an 8-week randomized, double-blind, placebo- controlled trial of guanfacine for the 170 children (ages 5-13 years) with PDD accompanied by hyperacti9vity and impulsiveness. Subjects who show a positive response will be invited to enter an 8-week Extension phase (treatment mask will not be broken). The treatment blind will be broken for children who do not achieve a positive response in the Double-blind phase. Children who show no change or deterioration on placebo will be treated with guanfacine in an 8-week Open-label phase. Children who show a partial response to guanfacine will be randomly assigned to a 4-week add on trial of methylphenidate or placebo to evaluate the potential benefits of combined treatment. We expect that 50 subjects will enter this pilot trial. The role of gene variants and urinary adrenergic/noradrenergic measures as biomarkers in moderating response to guanfacine on primary efficacy measures and adverse effects will be explored. PUBLIC HEALTH RELEVANCE: This study begins with a randomized trial of guanfacine in 170 children with Pervasive Developmental Disorders accompanied by hyperactivity. Methylphenidate or placebo will be added for children who show partial benefit to guanfacine.